Pharmaceutical tablets

ABSTRACT

The present invention relates to novel pharmaceutical tablets useful for administering pharmaceutical active ingredients, such as bisphosphonates. These tablets have improved surface properties which can aid esophageal transit, thereby reducing the potential for adverse gesture intestinal effects. The present invention also relates to processes for making said novel pharmaceutical tablets.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority of U.S. provisionalapplication Serial No. 60/141,987, filed Jul. 1, 1999.

FIELD OF THE INVENTION

[0002] The present invention relates to novel pharmaceutical tablets.These tablets have improved surface properties which can aid esophagealtransit, thereby reducing the potential for adverse gastrointestinaleffects. These compositions are useful for administering pharmaceuticalactive ingredients, such as bisphosphonates.

BACKGROUND OF THE INVENTION

[0003] The pharmaceutical industry employs various methods forcompounding pharmaceutical agents into oral tablet formulations.Standard methods for tablet formulation of bisphosphonic acids, however,suffer serious difficulties.

[0004] In particular, bisphosphonic acids which bear a basicnitrogen-containing functionality may interact with the lactose ofstandard formulations resulting in discoloration, instability andpotency loss. This degradation of the active ingredient is particularlypronounced in the presence of water and/or elevated temperatures. It isspeculated that this incompatibility is specifically due to the Maillard(or “browning”) reaction in which the free amino group of thebisphosphonic acid reacts with the “glycosidic” hydroxyl group of asugar (such as lactose) ultimately resulting in the formation of brownpigmented degradates. Although this problem may be avoided by theelimination if lactose, the use of lactose as an inert diluent isgenerally desirable.

[0005] The present invention solves this problem by providing a tabletformulation and process therefore that avoids such interaction betweenthe bisphosphonic acid and the lactose in the formulation. In additionthe present invention provides a processing advantage since it requiresonly blending of the ingredients without granulation or addition ofwater prior to compression.

[0006] In addition to compounding problems, bisphosphonates are poorlyabsorbed from the gastrointestinal tract. See B. J. Gertz et al.,Clinical Pharmacology of Alendronate Sodium, Osteoporosis Int., Suppl.3: S13-16 (1993) and B. J. Gertz et al., Studies of the oralbioavailability of alendronate, Clinical Pharnacology & Therapeutics,vol. 58, number 3, pp. 288-298 (September 1995), which are incorporatedby reference herein in their entirety. Intravenous administration hasbeen used to overcome this bioavailability problem. However, intravenousadministration is costly and inconvenient, especially when the patientmust be given an intravenous infusion lasting several hours on repeatedoccasions. If oral administration of the bisphosphonate is desired,relatively high doses must be administered to compensate for the lowbioavailability from the gastrointestinal tract. To offset this lowbioavailability, it is generally recommended that the patient take thebisphosphonate on an empty stomach and fast for at least 30 minutesafterwards. However, many patients find the need for such fasting on adaily basis to be inconvenient.

[0007] Moreover, oral administration of bisphosphonates has beenassociated with adverse gastrointestinal effects, especially thoserelating to the esophagus. See H. Fleisch, Bisphosphonates in BoneDisease, from the laboratory to the patient, third edition, 1997. Suchoral administration of bisphosphonates sometimes results in patientcomplaints shortly after dosing; said complaints are usuallycharacterized by the patients as heartburn, esophageal burning, painand/or difficulty upon swallowing, and/or pain existing behind and/ormid-sternum. It is believed that these complaints originate fromesophagitis or esophageal irritation caused by the erosion, ulceration,or other like irritation or the epithelial and mucosal tissues,resulting in the topical irritation thereof. If the dosage form adheresin the esophagus, the active ingredient slowly dissolves and creates ahigh drug concentration on the mucosal surface of the esophagus.

[0008] These unfavorable effects are exacerbated by the presence ofrefluxed gastric acid. For example, the bisphosphonate, pamidronate hasbeen associated with esophageal ulcers. See E. G. Lufkin et al.,Pamidronate: An Unrecognized Problem in Gastrointestinal Tolerability,Osteoporosis International, 4: 320-322 (1994), which is incorporated byreference herein in its entirety. Although not as common, the use ofalendronate has been associated with esophagitis and/or esophagealulcers. See P. C. De Groen, et al., Esophagitis Associated With The UseOfAlendronate, New England Journal of Medicine, vol. 335, no. 124, pp.1016-1021 (1996), D. O. Castell, Pill Esophagitis—The Case ofAlendronate, New England Journal of Medicine, vol. 335, no. 124, pp.1058-1059 (1996), and U. A. Liberman et al., Esophagitis andAlendronate, New England Journal of Medicine, vol. 335, no. 124, pp.1069-1070 (1996), which are incorporated by reference herein in theirentirety. The degree of adverse gastrointestinal effects ofbisphosphonates has been shown to increase with increasing dose. See C.H. Chestnut et al., Alendronate Treatment of the PostmenopausalOsteoporotic Woman: Effect of Multiple Dosages on Bone Mass and BoneRemodeling, The American Journal of Medicine, vol. 99, pp. 144-152,(August 1995), which is incorporated by reference herein in itsentirety. Also, these adverse esophageal effects appear to be moreprevalent in patients who do not take the bisphosphonate with anadequate amount of liquid or who lie down shortly after dosing, therebyincreasing the chance for esophageal reflux.

[0009] What is needed in the art is an oral bisphosphonate dosage formthat minimizes the adverse side effects enumerated above. Such a dosageform should prevent and/or lessen the degree of patient discomfort whilemaximizing the treatment by maintaining the bioavailability of thebisphosphonate.

[0010] However, dosage forms of bisphosphonates that are presently beingused are problematic. For example, rough, unpolished tablets are usefulin order to maintain the bioavailability of the active ingredient.Despite this benefit, the rough texture provides for poor esophagealtransit which causes the bisphosphonate to be released too early in theupper gastrointestinal tract, causing the patient discomfort.

[0011] To combat the premature release of active ingredient in the uppergastrointestinal tract, dosage forms have been developed to delay therelease of the active ingredients after passage through the uppergastrointestinal tract and in some cases through the stomach, i.e.,enteric coated tablets. However, enteric and completely coated tabletshave disadvantages because in certain instances its undesirable orunnecessary for a medicament to be in a delayed release dosage form.Additionally, enteric and completely coated tablets reduce thebioavailability of the active ingredient.

[0012] What is desired in the art are dosage forms that facilitate rapidesophageal transit, minimize or avoid the release of an activeingredient in the upper gastrointestinal tract, deliver the activeingredient to the stomach, and maintain the bioavailability of theactive ingredient.

[0013] The present invention solves this problem by providing a tabletformulation and process therefor that both facilitates esophagealtransit and maintains the bioavailability of the active ingredient. Thediscontinuous wax polish of the present invention has surprisingly beenfound to be useful for administering active agents such asbisphosphonates. These tablets with a discontinuous wax polish have theadvantage of providing rapid transit through the esophagus to minimizethe occurrence of adverse effects. The discontinuous wax coating orpolishing also has the advantage over enteric coated tablets of notinterfering with the bioavailability of the active ingredient. Thus, thecurrent invention provides a dosage form that eases and/or eliminatespatient discomfort after dosing while maintaining the bioavailability ofthe active ingredient.

[0014] It is an object of the invention to provide a pharmaceuticalcomposition, preferably a tablet comprising: an active ingredient, saidactive ingredient being a bisphosphonic acid or a pharmaceuticallyacceptable salt or ester thereof; excipients, said excipients comprisinga diluent, a binder, a disintegrant and a lubricant; and a discontinuouswax polish.

[0015] It is another object of the present invention to provide aprocess for the preparation of a tablet as described above.

[0016] These and other objects will become apparent to those of ordinaryskill from the teachings provided herein.

[0017] The application refers to a number of publications, patents andpatent applications the contents of which are hereby incorporated byreference in their entirety.

SUMMARY OF THE INVENTION

[0018] The present invention relates to novel pharmaceuticalcompositions, particularly tablets. These compositions have improvedsurface properties which can aid esophageal transit, thereby reducingthe potential for adverse gastrointestinal effects. These compositionsare useful for administering pharmaceutical active ingredients, such asbisphosphonates.

[0019] In one embodiment, the present invention relates to apharmaceutical tablet, comprising:

[0020] (a) from about 0.5 to 40% by weight of an active ingredientselected from the group consisting of a bisphosphonic acid or apharmaceutically acceptable salt or ester thereof; and

[0021] (b) from about 60 to 99.5% by weight of excipients, saidexcipients comprising a diluent selected from the group consisting ofanhydrous lactose or hydrous fast flow lactose, or mixtures thereof, abinder, a disintegrant, a lubricant; and a wax.

[0022] In another embodiment, the present invention relates to a processfor the preparation of a pharmaceutical tablet comprising;

[0023] (a) forming a mixture by mixing an active ingredient selectedfrom the group consisting of a bisphosphonic acid or a pharmaceuticallyacceptable salt or ester thereof, with a diluent, selected from thegroup consisting of anhydrous lactose or hydrous fast flow lactose, ormixtures thereof, a dry binder, a disintegrant, and optionally one ormore additional ingredients selected from the groups consisting of:compression aids, flavors, flavor enhancers, sweeteners andpreservatives;

[0024] (b) lubricating the mixture with a lubricant;

[0025] (c) compressing the resultant lubricated mixture into a desiredtablet form; and

[0026] (d) coating the desired tablet with a wax to form a discontinuouswax polish.

[0027] All percentages and ratios used herein, unless otherwiseindicated, are by weight. The invention hereof can comprise, consist of,or consist essentially of the essential as well as optional ingredients,components, and methods described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention relates to novel pharmaceuticalcompositions, particularly tablets, that are useful for administeringpharmaceutical active ingredients, such as bisphosphonates. Thecompositions of the present invention are coated with a discontinuouswax polish that enables the compositions to have improved surfaceproperties such as rapid esophageal transit of the composition, whichreduces the potential for adverse gastrointestinal effects. The improvedsurface properties due to the discontinuous wax polish also enable thecompositions to maintain the bioavailability of the active ingredient,thereby preserving the active ingredient's potency.

[0029] The present invention is characterized by pharmaceuticalcompositions comprising from about 0.5 to 40% by weight of an activeingredient, said active ingredient being a bisphosphonic acid or apharmaceutically acceptable salt or ester thereof; from about 60 to99.5% by weight of excipients, said excipients comprising a diluentselected from the group consisting of anhydrous lactose or hydrous fastflow lactose, a binder, a disintegrant, a lubricant; and a discontinuouswax polish.

[0030] Preferably, the bisphosphonic acid or pharmaceutically acceptablesalt or ester thereof is a nitrogen containing bisphosphonate orpharmaceutically acceptable salt thereof.

[0031] More preferably, the nitrogen containing bisphosphonate orpharmaceutically acceptable salt thereof is selected from the groupconsisting of:

[0032] 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

[0033] N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

[0034] 4-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonicacid;

[0035] 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;

[0036] 3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonicacid;

[0037] 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonicacid;

[0038] 1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bisphosphonic acid; and

[0039] 4-(hydroxymethylene-1,1-bisphosphonic acid)piperidene;

[0040] or a pharmaceutically acceptable salt thereof.

[0041] More preferably, the nitrogen containing bisphosphonic acid orpharmaceutically acceptable salt thereof is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or a pharmaceuticallyacceptable salt thereof.

[0042] Most preferably, the nitrogen containing bisphosphonic acid orpharmaceutically acceptable salt thereof is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salttrihydrate.

[0043] The present invention is also characterized by to pharmaceuticalcompositions comprising from about 0.5 to 40% by weight of an activeingredient, said active ingredient being a bisphosphonic acid or apharmaceutically acceptable salt thereof; from about 60 to 99.5% byweight of excipients, said excipients comprising a diluent selected fromthe group consisting of anhydrous lactose or hydrous fast flow lactose,a binder, a disintegrant, a lubricant; and a discontinuous wax polish;wherein said pharmaceutical composition is in a desired tablet form.

[0044] Preferably, the bisphosphonic acid or pharmaceutically acceptablesalt thereof is a nitrogen containing bisphosphonate or pharmaceuticallyacceptable salt thereof.

[0045] More preferably, the nitrogen containing bisphosphonate orpharmaceutically acceptable salt thereof is selected from the groupconsisting of:

[0046] 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

[0047] N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

[0048] 4-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonicacid;

[0049] 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;

[0050] 3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonicacid;

[0051] 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonicacid;

[0052] 1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bisphosphonic acid; and

[0053] 4-(hydroxymethylene-1,1-bisphosphonic acid)piperidene;

[0054] or a pharmaceutically acceptable salt thereof.

[0055] More preferably, the nitrogen containing bisphosphonic acid orpharmaceutically acceptable salt thereof is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or a pharmaceuticallyacceptable salt thereof.

[0056] Most preferably, the nitrogen containing bisphosphonic acid orpharmaceutically acceptable salt thereof is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salttrihydrate.

[0057] The present invention also relates to processes for theproduction of pharmaceutical compositions and tablets. The processesinclude coating the compositions or tablets with a discontinuous waxpolish which provides advantages over completely coated compositions andtablets. Because the compositions or tablets are discontinuously coated,the bioavailability of the active ingredient is preserved.

[0058] The present invention is also characterized by processes for thepreparation of a tablet containing an active ingredient, said activeingredient being a bisphosphonic acid or a pharmaceutically acceptablesalt thereof; which process comprises:

[0059] forming a mixture by mixing the active ingredient with:

[0060] a diluent, selected from the group consisting of anhydrouslactose and hydrous fast flow lactose and mixtures thereof,

[0061] a dry binder,

[0062] a disintegrant,

[0063] and optionally one or more additional ingredients selected fromthe groups consisting of: compression aids, flavors, flavor enhancers,sweeteners and preservatives;

[0064] lubricating the mixture with a lubricant;

[0065] compressing the resultant lubricated mixture into a desiredtablet form; and

[0066] coating the desired tablet form with a discontinuous wax polish.

[0067] Preferably, the bisphosphonic acid or pharmaceutically acceptablesalt thereof is a nitrogen containing bisphosphonate or pharmaceuticallyacceptable salt thereof.

[0068] More preferably, the nitrogen containing bisphosphonate orpharmaceutically acceptable salt thereof is selected from the groupconsisting of:

[0069] 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

[0070] N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

[0071] 4-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonicacid;

[0072] 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;

[0073] 3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bi sphosphonicacid;

[0074] 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonicacid;

[0075] 1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bisphosphonic acid; and

[0076] 4-(hydroxymethylene-1,1-bisphosphonic acid)piperidene;

[0077] or a pharmaceutically acceptable salt thereof.

[0078] More preferably, the nitrogen containing bisphosphonic acid orpharmaceutically acceptable salt thereof is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or a pharmaceuticallyacceptable salt thereof.

[0079] Most preferably, the nitrogen containing bisphosphonic acid orpharmaceutically acceptable salt thereof is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salttrihydrate.

[0080] Preferably, the dry binder is microcrystalline cellulose.

[0081] Preferably, the disintegrant is selected from the groupconsisting of modified starch, modified cellulose polymer, andcroscarmellose sodium, or a combination thereof.

[0082] More preferably, the disintegrant is croscarmellose sodium.

[0083] Preferably, the lubricant is magnesium stearate.

[0084] Preferably, no additional water is added to the mixture prior tocompressing.

[0085] Preferably, the processes are carried out at ambient temperature.

[0086] More preferably, no additional water is added to the mixtureprior to compressing and said process is carried out at ambienttemperature.

[0087] The word wax, which had originally referred to relatively highmelting animal or vegetable derived lipids, is applied to a largevariety of chemically different lipids in modern parlance. Included aswaxes are animal waxes, plant waxes, mineral waxes and petroleum waxes.See International Cosmetic Ingredient Dictionary and Handbook, SeventhEdition, vol. 1, p. 1604-05 (1997), which is hereby incorporated byreference in its entirety.

[0088] Preferably, the discontinuous wax polish is selected from thegroup consisting of: apple peel wax, avocado wax, bayberry wax, beeswax,candelilla wax, carnauba wax, ceresin, cetyl esters, hydrogenated jojobaoil, hydrogenated jojoba wax, hydrogenated microcrystalline wax,hydrogenated rice bran wax, hydrolyzed beeswax, jojoba butter, jojobaesters, jojoba wax, lanolin wax, microcrystalline wax, mink wax, montanacid wax, mantan wax, orange peel wax, ouricury wax, oxidized beeswax,oxidized microcrystalline wax, ozokerite, palm kernel wax, paraffin,PEG-6 Beeswax, PEG-8 Beeswax, PEG-12 Beeswax, PEG-20 Beeswax, PEG-12Carnauba, potassium oxidized microcrystalline wax, rice wax, shellacwax, spent grain wax, sulfurized jojoba oil, synthetic beeswax,synthetic candelilla wax, synthetic carnauba, synthetic Japan wax,synthetic jojoba oil, synthetic wax, and mixtures thereof.

[0089] More preferably, the discontinuous wax polish is carnauba wax.

[0090] Carnauba wax, which is also known as brazil wax or caranda wax,is the hardest and highest melting of the waxes commonly used inpharmaceutical formulations. It can be used as an aqueous emulsion or apowder to polish tablets. See Handbook of Pharmaceutical Excipients,Second Edition, p. 552 (1994), which is hereby incorporated by referencein its entirety.

[0091] Beeswax can be obtained naturally (yellow beeswax) or chemicallybleached (white beeswax). Beeswax consists of 70-75% of a mixture ofvarious esters of straight chain monohydric alcohols with even numbercarbon chains, the chief ester being myricyl palmitate. Beeswax isprimarily used as a stiffening agent, an emulsifier, or a polishingagent for tablets. See Handbook of Pharmaceutical Excipients, SecondEdition, p. 558-60 (1994).

[0092] Microcrystalline wax, which is also known as amorphous wax andpetroleum ceresin, is used to modify the crystal structure of otherwaxes present in a mixture so that changes in crystal structure, whichare usually exhibited over a period of time, do not occur.Microcrystalline wax also prevents blends of waxes from sweating orbleeding. See Handbook of Pharmaceutical Excipients, Second Edition, p.554 (1994).

[0093] Paraffin, which is also known as hard wax, paraffinium solidum,and paraffinium durum, is a purified mixture of solid saturatedhydrocarbons having the general formula C_(n)H_(2n)+2. It is generallyobtained from petroleum or shale oil. See Handbook of PharmaceuticalExcipients, Second Edition, p. 327 (1994).

[0094] Cetyl esters wax, which is also known as spermaceti waxreplacement and synthetic spermaceti, is a mixture consisting primarilyof esters of saturated fatty alcohols and saturated fatty acids. SeeHandbook of Pharmaceutical Excipients, Second Edition, p. 104(1994).

[0095] Shellac wax, which is also known as lacca and lac, is a naturallyoccurring material that is used in pharmaceutical formulations for thecoating of tablets. Shellac wax is usually applied as a 35% w/valcoholic solution, but is also applied as a 40% w/v alcoholic solutionwhen sealing tablets to protect them from moisture before being film orsugar coated. Shellac is insoluble in acidic conditions but soluble athigher pHs. See Handbook of Pharmaceutical Excipients, Second Edition,p. 422-23 (1994).

[0096] The pharmaceutical compositions and tablets of the presentinvention are generally administered to mammals in need ofbisphosphonate therapy. Preferably the mammals are human patients,particularly human patients in need of inhibiting bone resorption, suchas patients in need of treating or preventing abnormal bone resorption.

[0097] The pharmaceutical compositions and tablets of the presentinvention are especially useful in administering bisphosphonate therapyto human patients that have been identified as suffering from or aresusceptible to upper gastrointestinal disorders, e.g. GERD, esophagitis,dyspepsia, ulcers, etc. In such patients conventional bisphosphonatetherapy could potentially exacerbate or induce such uppergastrointestinal disorders.

[0098] The term “discontinuous wax polish,” as used herein, means a waxpolish that is not continuously applied to the surface area of apharmaceutical tablet. Accordingly, the wax polish is applied to thepharmaceutical tablet such that about 1 to 99% of the surface area ofthe tablet is coated with wax polish.

[0099] The term “pharmaceutical tablet,” as used herein, means a soliddosage form that contains a excipients and a pharmaceutically effectiveamount of bisphosphonate compound that will elicit the desiredtherapeutic effect or response when administered in accordance with thedesired treatment regimen.

[0100] The term “surface area,” as used herein, means the exterior areaof a pharmaceutical tablet.

[0101] The term “pharmaceutically effective amount”, as used herein,means that amount of the bisphosphonate compound, that will elicit thedesired therapeutic effect or response when administered in accordancewith the desired treatment regimen. A preferred pharmaceuticallyeffective amount of the bisphosphonate is a bone resorption inhibitingamount.

[0102] The term “minimize the occurrence of or potential for adversegastrointestinal effects”, as used herein, means reducing, preventing,decreasing, or lessening the occurrence of or the potential forincurring unwanted side effects in the gastrointestinal tract, i.e. theesophagus, stomach, intestines, and rectum, particularly the uppergastrointestinal tract, i.e. the esophagus and stomach. Non-limitingadverse gastrointestinal effects include, but are not limited to GERD,esophagitis, dyspepsia, ulcers, esophageal irritation, esophagealperforation, abdominal pain, and constipation.

[0103] The term “pharmaceutically acceptable” as used herein means thatthe salts and derivatives of the bisphosphonates have the same generalpharmacological properties as the free acid form from which they arederived and are acceptable from a toxicity viewpoint.

[0104] The term “pharmaceutically acceptable salt”, as used hereinrefers to non-toxic salts of the compounds useful in the instantinvention which are generally prepared by reacting the free base with asuitable organic or inorganic acid. Representative salts include thefollowing: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),palmitate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide and valerate. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include alkali metalsalts, e.g., sodium or potassium salts; alkaline earth metal salts,e.g., calcium or magnesium salts; and salts formed with suitable organicligands, e.g., quaternary ammonium salts. Pharmaceutically acceptablesalts also specifically include hydrates as well as the anhydrous forms.

[0105] Dosage regimens utilizing the compounds of the present inventionare selected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient orsubject; the severity of the condition to be treated; the route ofadministration; the renal and hepatic function of the patient orsubject; and the particular compound or salt thereof employed. Anordinarily skilled physician, veterinarian or clinician can readilydetermine and prescribe the effective amount of the drug required toreduce the risk of, counter or arrest the progress of the condition.

[0106] Oral dosages of the present invention, when used for theindicated effects, will range between about 0.05 mg per kg of bodyweight per day (mg/kg/day) to about 1.0 mg/kg/day. For example, as atreatment, alendronate would be administered to mammals in preferreddoses of about 2.5 mg to about 50 mg daily, preferably about 5 mg forosteoporosis treatment and about 10 mg for osteoporosis prevention, andabout 40 mg Paget's disease. Alternatively, dosages of about 8.75 toabout 70 mg once-weekly or twice-weekly. Preferred weekly dosages areabout 35 mg, e.g., for osteoporosis prevention and about 70 mg, e.g.,for osteoporosis treatment. Preferred twice-weekly dosage are about 17.5mg, e.g., for osteoporosis prevention and about 35 mg, e.g., forosteoporosis treatment. The dosages may be varied over time, such that apatient may receive a high dose, such as 20 mg/day for a treatmentperiod, such as two years, followed by a lower dose thereafter, such as5 mg/day thereafter. Alternatively, a low dose (i.e. approximately 5 mg)may also be administered for a longer term with similar beneficialeffects. Oral doses of the present invention can be administered in asingle daily dose or in a divided dose.

[0107] Bisphosphonates

[0108] The methods and compositions of the present invention comprisethe administration of a bisphosphonate or a pharmaceutically acceptablesalt thereof. The bisphosphonates of the present invention correspond tothe chemical formula

[0109] wherein n is an integer from 0 to 7 and wherein A and X areindependently selected from the group consisting of H, OH, halogen, NH₂,SH, phenyl, C1-C30 alkyl, C3-C30 branched or cycloalkyl, C1-C30substituted alkyl, C1-C10 alkyl substituted NH₂, C3-C10 branched orcycloalkyl substituted NH₂, C1-C10 dialkyl substituted NH₂, C1-C10alkoxy, C1-C10 alkyl substituted thio, thiophenyl, halophenylthio,C1-C10 alkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl,imidazolyl, imidazopyridinyl, and benzyl, such that both A and X are notselected from H or OH when n is 0; or A and X are taken together withthe carbon atom or atoms to which they are attached to form a C3-C10ring.

[0110] In the foregoing chemical formula, the alkyl groups can bestraight, branched, or cyclic, provided sufficient atoms are selectedfor the chemical formula. The C1-C30 substituted alkyl can include awide variety of substituents, non-limiting examples which include thoseselected from the group consisting of phenyl, pyridyl, furanyl,pyrrolidinyl, imidazonyl, NH₂, C1-C10 alkyl or dialkyl substituted NH₂,OH, SH, and C₁-C10 alkoxy.

[0111] The foregoing chemical formula is also intended to encompasscomplex carbocyclic, aromatic and hetero atom structures for the Aand/or X substituents, non-limiting examples of which include naphthyl,quinolyl, isoquinolyl, adamantyl, and chlorophenylthio.

[0112] A non-limiting class of structures useful in the instantinvention are those in which A is selected from the group consisting ofH, OH, and halogen, and X is selected from the group consisting ofC1-C30 alkyl, C1-C30 substituted alkyl, halogen, and C1-C10 alkyl orphenyl substituted thio.

[0113] A non-limiting subclass of structures useful in the instantinvention are those in which A is selected from the group consisting ofH, OH, and Cl, and X is selected from the group consisting of C1-C30alkyl, C1-C30 substituted alkyl, Cl, and chlorophenylthio.

[0114] A non-limiting example of the subclass of structures useful inthe instant invention is when A is OH, X is a 3-aminopropyl moiety and nis zero, so that the resulting compound is a4-amino-1,-hydroxybutylidene-1,1-bisphosphonate, i.e. alendronate.

[0115] Pharmaceutically acceptable salts and derivatives of thebisphosphonates are also useful herein. Non-limiting examples of saltsinclude those selected from the group consisting alkali metal, alkalinemetal, ammonium, and mono-, DI, tri-, or tetra-C1-C30-alkyl-substitutedammonium. Preferred salts are those selected from the group consistingof sodium, potassium, calcium, magnesium, and ammonium salts.Non-limiting examples of derivatives include those selected from thegroup consisting of esters, hydrates, and amides.

[0116] It should be noted that the terms “bisphosphonate” and“bisphosphonates”, as used herein in referring to the therapeutic agentsof the present invention are meant to also encompass diphosphonates,biphosphonic acids, and diphosphonic acids, as well as salts andderivatives of these materials. The use of a specific nomenclature inreferring to the bisphosphonate or bisphosphonates is not meant to limitthe scope of the present invention, unless specifically indicated.Because of the mixed nomenclature currently in use by those or ordinaryskill in the art, reference to a specific weight or percentage of abisphosphonate compound in the present invention is on an acid activeweight basis, unless indicated otherwise herein. For example, the phrase“about 5 mg of a bone resorption inhibiting bisphosphonate selected fromthe group consisting of alendronate, pharmaceutically acceptable saltsthereof, and mixtures thereof, on an alendronic acid active weightbasis” means that the amount of the bisphosphonate compound selected iscalculated based on 5 mg of alendronic acid.

[0117] Non-limiting examples of bisphosphonates useful herein includethe following:

[0118] Alendronic acid, 4-amino-1-hydroxybutylidene-1,1-bisphosphonicacid.

[0119] Alendronate (also known as alendronate sodium or alendronatemonosodium trihydrate), 4-amino-1-hydroxybutylidene-1,1-bisphosphonicacid monosodium trihydrate.

[0120] Alendronic acid and alendronate are described in U.S. Pat. No.4,922,007, to Kieczykowski et al., issued May 1, 1990; U.S. Pat. No.5,019,651, to Kieczykowski et al., issued May 28, 1991; U.S. Pat. No.5,510,517, to Dauer et al., issued Apr. 23, 1996; U.S. Pat. No.5,648,491, to Dauer et al., issued Jul. 15, 1997, all of which areincorporated by reference herein in their entirety.

[0121] Cycloheptylaminomethylene-1,1-bisphosphonic acid, YM 175,Yamanouchi (cimadronate), as described in U.S. Pat. No. 4,970,335, toIsomura et al., issued Nov. 13, 1990, which is incorporated by referenceherein in its entirety.

[0122] 1,1-dichloromethylene-1,1-diphosphonic acid (clodronic acid), andthe disodium salt (clodronate, Procter and Gamble), are described inBelgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967), both ofwhich are incorporated by reference herein in their entirety.

[0123] 1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonic acid(EB-1053).

[0124] 1-hydroxyethane-1,1-diphosphonic acid (etidronic acid).

[0125] 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonicacid, also known as BM-210955, Boehringer-Mannheim (ibandronate), isdescribed in U.S. Pat. No. 4,927,814, issued May 22, 1990, which isincorporated by reference herein in its entirety.

[0126] 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate).

[0127] 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid(olpadronate).

[0128] 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid(pamidronate).

[0129] [2-(2-pyridinyl)ethylidene]-1,1-bisphosphonic acid (piridronate)is described in U.S. Pat. No. 4,761,406, which is incorporated byreference in its entirety.

[0130] 1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid(risedronate).

[0131] (4-chlorophenyl)thiomethane-1,1-disphosphonic acid (tiludronate)as described in U.S. Pat. No. 4,876,248, to Breliere et al., Oct. 24,1989, which is incorporated by reference herein in its entirety.

[0132] 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid(zolendronate).

[0133] A non-limiting class of bisphosphonates useful in the instantinvention are selected from the group consisting of alendronate,cimadronate, clodronate, tiludronate, etidronate, ibandronate,risedronate, piridronate, pamidronate, zolendronate, pharmaceuticallyacceptable salts thereof, and mixtures thereof.

[0134] A non-limiting subclass of the above-mentioned class useful inthe instant case contains alendronate, pharmaceutically acceptable saltsthereof, and mixtures thereof.

[0135] A non-limiting example of the subclass is alendronate monosodiumtrihydrate.

[0136] Pharmaceutical Compositions

[0137] The compounds of the present invention can be administered insuch oral dosage forms as tablets, capsules (each of which includessustained release or timed release formulations), pills, powders,granules, elixirs, tinctures, suspensions, syrups, pastes, gels,solutions, and emulsions. Likewise, they may also be administered inintravenous (bolus or infusion), intraperitoneal, topical (e.g., oculareyedrop), subcutaneous, intramuscular or transdermal (e.g., patch) form,all using forms well known to those of ordinary skill in thepharmaceutical arts. An effective but non-toxic amount of the compounddesired can be employed as a treatment for dental resorptive lesions.

[0138] Compositions useful in the present invention comprise apharmaceutically effective amount of a bisphosphonate or apharmaceutically acceptable salt thereof. The bisphosphonate istypically administered in admixture with suitable pharmaceuticaldiluents, excipients, or carriers, collectively referred to herein as“carrier materials”, suitably selected with respect to oraladministration, i.e. tablets, capsules, elixirs, syrups, effervescentcompositions, powders, and the like, and consistent with conventionalpharmaceutical practices. For example, for oral administration in theform of a tablet, capsule, or powder, the active ingredient can becombined with an oral, non-toxic, pharmaceutically acceptable inertcarrier such as lactose, starch, sucrose, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, croscarmellose sodium and thelike; for oral administration in liquid form, e.g., elixirs and syrups,effervescent compositions, the oral drug components can be combined withany oral, non-toxic, pharmaceutically acceptable inert carrier such asethanol, glycerol, water and the like. Moreover, when desired ornecessary, suitable binders, lubricants, disintegrating agents, buffers,coatings, and coloring agents can also be incorporated. Suitable binderscan include starch, gelatin, natural sugars such a glucose, anhydrouslactose, free-flow lactose, beta-lactose, and corn sweeteners, naturaland synthetic gums, such as acacia, guar, tragacanth or sodium alginate,carboxymethyl cellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. A tablet formulations for alendronate monosodiumtrihydrate and other bisphosphonates are described in U.S. Pat. No.5,358,941, to Bechard et al, issued Oct. 25, 1994, and U.S. Pat. No.5,681,590, to Bechard et al., issued Oct. 28, 1997, which are bothincorporated by reference herein in its entirety. Oral liquidalendronate formulations are described in U.S. Pat. No. 5,462,932, toBrenner et al, issued Oct. 31, 1995, which is incorporated by referenceherein in its entirety. Intravenous alendronate formulations aredescribed in U.S. Pat. No. 5,780,455, to Brenner et al, issued Jul. 14,1998, which is incorporated by reference herein in its entirety. Thecompounds used in the present method can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxylpropyl-methacrylamide, and the like.

[0139] The precise dosage of the bisphonate will vary with the dosingschedule, the oral potency of the particular bisphosphonate chosen, theage, size, sex and condition of the mammal or human, the nature andseverity of the disorder to be treated, and other relevant medical andphysical factors. Thus, a precise pharmaceutically effective amountcannot be specified in advance and can be readily determined by thecaregiver or clinician. Appropriate amounts can be determined by routineexperimentation from animal models and human clinical studies.Generally, an appropriate amount of bisphosphonate is chosen to obtain adental resorptive lesion inhibiting effect.

EXAMPLES

[0140] The following examples further describe and demonstrateembodiments within the scope of the present invention. The examples aregiven solely for the purpose of illustration and are not to be construedas limitations of the present invention as many variations thereof arepossible without departing from the spirit and scope of the invention.

[0141] Pharmaceutical Tablet Compositions

[0142] Tablets are prepared using standard mixing and formationtechniques as described in U.S. Pat. No. 5,358,941, to Bechard et al.,issued Oct. 25, 1994, which is incorporated by reference herein in itsentirety. The tablets are polished with a discontinuous film of thedesired wax using a coating pan, a coating column, a blender, orequivalent equipment.

[0143] For example, tablets containing about 10 mg or 70 mg ofalendronate monosodium trihydrate, on an alendronic acid active basis,are prepared using the following relative weights of ingredients. 10 mgTablet 70 mg Tablet Ingredient Per Tablet Per Tablet AlendronateMonosodium 13.05 mg 91.37 mg Trihydrate Anhydrous Lactose, NF 104 mg 114mg Microcrystalline Cellulose, 80 mg 140 mg NF Magnesium Stearate, NF 1mg 1.75 mg Croscarmellose Sodium, NF 2 mg 3.5 mg Carnauba Wax 0.2 mg 0.2mg

[0144] The resulting tablets are useful for administration in accordancewith the methods of the present invention for inhibiting boneresorption.

[0145] Similarly, tablets comprising other relative weights ofalendronate, on an alendronic acid active basis are prepared: e.g.,tablets containing about 5, 8.75, 17.5, 35 and 140 mg per tablet. Also,tablets containing other bisphosphonates at appropriate active levelsare similarly prepared: e.g., cimadronate, clodronate, tiludronate,etidronate, ibandronate, risedronate, piridronate, pamidronate,zolendronate, and pharmaceutically acceptable salts thereof. Also,tablets containing combinations of bisphosphonates are similarlyprepared.

What is claimed is:
 1. A pharmaceutical tablet, comprising: (a) fromabout 0.5 to 40% by weight of an active ingredient selected from thegroup consisting of a bisphosphonic acid or a pharmaceuticallyacceptable salt or ester thereof; and (b) from about 60 to 99.5% byweight of excipients, said excipients comprising a diluent selected fromthe group consisting of anhydrous lactose or hydrous fast flow lactose,or mixtures thereof, a binder, a disintegrant, a lubricant; and a wax.2. A pharmaceutical tablet according to claim 2 wherein said wax isselected from the group consisting of apple peel wax, avocado wax,bayberry wax, beeswax, candelilla wax, carnauba wax, ceresin, cetylesters, hydrogenated jojoba oil, hydrogenated jojoba wax, hydrogenatedmicrocyrstalline wax, hydrogenated rice bran wax, hydrolyzed beeswax,jojoba butter, jojoba esters, jojoba wax, lanolin wax, microcrystallinewax, mink wax, montan acid wax, montan wax, orange peel wax, ouricurywax, oxidized beeswax, oxidized micorcrystalline wax, ozokerite, palmkernel wax, paraffin wax, paraffin, PEG-6 beeswax, PEG-8 beeswax, Peg-12beeswax, PEG-20 beeswax, PEG-12 carnauba, potassium oxidizedmicrocrystalline wax, rice wax, shellac wax, spent grain wax, sulfurizedjojoba oil, synthetic beeswax, synthetic candelilla wax, syntheticcarcauba, synthetic japan wax, synthetic jojoba oil, synthetic wax, andmixtures thereof.
 3. A pharmaceutical tablet according to claim 3wherein said bisphosphonic acid is selected from the group consisting of4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;4-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bisphosphonic acid; and4-(hydroxymethylene-1,1-bisphosphonic acid)piperidene; or apharmaceutically acceptable salt or ester thereof.
 4. A pharmaceuticaltablet according to claim 3 wherein said bisphosphonic acid is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or a pharmaceuticallyacceptable salt thereof.
 5. A pharmaceutical tablet according to claim 4wherein said bisphosphonic acid is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salttrihydrate.
 6. A pharmaceutical tablet according to claim 5 wherein saiddiluent is anhydrous lactose, said binder is microcrystalline cellulose,said disintegrant is croscarmellose sodium, and said lubricant ismagnesium stearate.
 7. A pharmaceutical tablet according to claim 1wherein said wax is present as a discontinuous wax polish.
 8. Apharmaceutical tablet according to claim 7 wherein said wax is carnaubawax.
 9. A pharmaceutical tablet according to claim 8 comprising fromabout 5 mg to about 70 mg, on a bisphosphonic acid active basis of saidbisphosphonic acid.
 10. A process for the preparation of apharmaceutical tablet comprising; (a) forming a mixture by mixing anactive ingredient selected from the group consisting of a bisphosphonicacid or a pharmaceutically acceptable salt or ester thereof, with adiluent, selected from the group consisting of anhydrous lactose orhydrous fast flow lactose, or mixtures thereof, a dry binder, adisintegrant, and optionally one or more additional ingredients selectedfrom the groups consisting of: compression aids, flavors, flavorenhancers, sweeteners and preservatives; (b) lubricating the mixturewith a lubricant; (c) compressing the resultant lubricated mixture intoa desired tablet form; and (d) coating the desired tablet with a wax toform a discontinuous wax polish.
 11. A process according to claim 10wherein said wax is selected from the group consisting of apple peelwax, avocado wax, bayberry wax, beeswax, candelilla wax, carnauba wax,ceresin, cetyl esters, hydrogenated jojoba oil, hydrogenated jojoba wax,hydrogenated microcyrstalline wax, hydrogenated rice bran wax,hydrolyzed beeswax, jojoba butter, jojoba esters, jojoba wax, lanolinwax, microcrystalline wax, mink wax, montan acid wax, montan wax, orangepeel wax, ouricury wax, oxidized beeswax, oxidized micorcrystalline wax,ozokerite, palm kernel wax, paraffin wax, paraffin, PEG-6 beeswax, PEG-8beeswax, Peg-12 beeswax, PEG-20 beeswax, PEG-12 camauba, potassiumoxidized microcrystalline wax, rice wax, shellac wax, spent grain wax,sulfurized jojoba oil, synthetic beeswax, synthetic candelilla wax,synthetic carcauba, synthetic japan wax, synthetic jojoba oil, syntheticwax, and mixtures thereof.
 12. A process according to claim 11 whereinsaid bisphosphonic acid is selected from the group consisting of4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;4-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;1-hydroxy-2-[3-pyridyl]ethylidene-1,1-bisphosphonic acid; and4-(hydroxymethylene-1,1-bisphosphonic acid)piperidene; or apharmaceutically acceptable salt or ester thereof.
 13. A processaccording to claim 12 wherein said bisphosphonic acid is4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or a pharmaceuticallyacceptable salt thereof.
 14. A process according to claim 13 whereinsaid bisphosphonic acid is 4-amino-1-hydroxybutylidene-1,1-bisphosphonicacid monosodium salt trihydrate
 15. A process according to claim 14wherein said diluent is anhydrous lactose, said binder ismicrocrystalline cellulose, said disintegrant is croscarmellose sodium,and said lubricant is magnesium stearate.
 16. A process according toclaim 15 wherein no additional water is added to the mixture prior tocompressing.
 17. A process according to claim 16 wherein said process iscarried out at ambient temperature
 18. The process according to claim 17wherein the discontinuous wax polish is carnauba wax.